Central nervous system (CNS) myelin is the target of an immune attack in multiple sclerosis (MS). The precise target(s) and the molecular mechanisms responsible for immunopathology have not been elucidated. Proteolipid protein (PLP) is the major protein component of DNS myelin and is now recognized as a major autoantigen involved in the development of experimental allergic encephalomyelitis (EAE) an experimental model for human MS. To determine the role of PLP in this disease process, I propose to study the cellular and molecular mechanisms involved in the induction of the autoimmune response to PLP in EAE. We have developed T cell clones specific for encephalitogenic determinants of myelin PLP residues 139-151 (HSLGKWLGHPDKF) and PLP 103-116 (YKTTICGKGLSATV) in SJL and SWR mice, respectively. Most of these clones induce EAE upon transfer into mice. The PLP specific T cell clones from both strains show considerable heterogeneity in T cell receptor usage. We hypothesize that the severe EAE produced by sensitization with encephalitogenic PLP peptides may be due to recruitment of a large/diverse population of T cells. This diversity could be generated either by recognition of multiple T cell epitopes in each PLP determinant or by a lack of deletion of PLP reactive T cells during development in the thymus. We will i) analyze and compare the diversity of the T cell responses to the encephalitogenic PLP determinants in mouse strains that either express or lack a class II MHC molecule (IE) and differ in their expression of some of the TcR Vbeta gene segments; ii) determine whether the diversity is due to multiple epitopes within a single encephalitogenic PLP determinant and iii) study the effect of neonatal tolerance on the development of the T cell repertoire to PLP. The results will provide broad basic information on the nature of autoimmune responses to encephalitogenic PLP determinants which may be relevant to understanding the immunological events occurring in multiple sclerosis and other diseases potentially mediated by autoimmune mechanisms.